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Differences in lipoprotein concentration and composition modify the plasma distribution of free and liposomal
1Division of Pharmaceutics and Biopharmaceutics, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Purpose:
The purpose of these studies were to determine the distribution of a lipophilic antineoplastic agent, annamycin (Ann), and its liposomal counterpart (LAnn) in plasma which had been altered in its lipoprotein concentration and lipid composition.
Methods:
Ann, LAnn, and doxorubicin (a hydrophilic control) were incubated in human plasma for 1 hour at 37 degrees C. Following incubation plasma samples were assayed by fluorimetry for drug in each of the lipoprotein and lipoprotein-deficient plasma (LPDP) fractions. To assess the influence of modified lipoprotein concentrations and lipid composition on plasma distribution of Ann and LAnn, either Ann or LAnn were incubated in human plasma which had been supplemented with very low density lipoproteins (VLDL) or low density lipoproteins (LDL).
Results:
When unbound Ann or doxorubicin was incubated in plasma for 1 hour at 37 degrees C, the majority of drug was found in the LPDP fraction. However, when Ann was incorporated into liposomes composed of dimyristoylphosphatidylcholine and dimyristoylphosphatidylglycerol (LAnn) the majority of Ann was recovered in the high-density lipoprotein (HDL) fraction. Elevation of plasma LDL-cholesterol or VLDL-triglyceride concentrations increased the amounts of Ann and LAnn associated with these lipoprotein classes. Alterations in HDL composition decreased the amount of Ann, but increased the amount of L-Ann within the HDL fraction. Lipid transfer protein (LTP) activity did not significantly modify the plasma distribution of Ann and LAnn in short-term experiments, but the modified lipoprotein composition that LTP facilitates in long-term incubations reduced the capacity of VLDL and LDL to accept drug.
Conclusions:
These findings suggest that lipoprotein concentration and composition alter the plasma distribution of Ann and LAnn and may help to explain the discrepancies observed in the pharmacokinetics of Ann and LAnn when they are administered to healthy versus cancer patients.